There is growing evidence suggesting that autoimmune T cell responses to myelin antigens, including myelin basic protein (MBP), are engaged in the pathogenesis of multiple sclerosis (MS) (Stinissen et al., Crit. Rev. Immunol. 1997; 17:33-75). MBP-reactive T cells are found to undergo in vivo activation and occur at high precursor frequency in the blood and cerebrospinal fluid of patients with MS (Zhang et al., J. Exp. Med., 1994; 179:973-984; Chou et al., J. Neuroimmunol., 1992; 38:105-114; Allegretta et al., Science, 1990; 247:718-721). These MBP-reactive T cells produce pro-inflammatory Th1 cytokines (IL-2, TNF-α and γ-interferon) and are thought to facilitate myelin-destructive inflammation in the central nervous system (Sharief et al., N. Engl. J. Med., 1991; 325:467-472; Selmaj et al., J. Clin. Invest., 1991; 87:949-954). It has been shown that MBP-reactive T cells can induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS (Ben-Nun et al., Eur. J. Immunol., 1981; 11:195-204). EAE can also be prevented or cured by repeated inoculations with MBP-reactive T cells that have been inactivated by chemical treatment or irradiation, a treatment procedure termed T cell vaccination (Ben-Nun et al., Nature, 1981; 292:60-61). It has been demonstrated that T cell vaccination induces regulatory immune responses comprised of anti-idiotypic T cells and anti-ergotypic T cells, which contribute to the treatment effects on EAE and other experimental autoimmune disease models (Lider et al., Science, 1988; 239:820-822; Lohse et al., Science, 1989; 244: 820-822).
T cell vaccination has been advanced recently to clinical trials in patients with MS based on the hypothesis that depletion of MBP-reactive T cells may improve the clinical course of the disease. In a pilot clinical trial, we demonstrated that vaccination with irradiated autologous MBP-reactive T cell clones elicited CD8+ cytolytic T cell responses that specifically recognized and lysed MBP-reactive T cells used for vaccination (Zhang et al., Science, 1993; 261: 1451-1454, Medear et al., Lancet 1995: 346:807-808). Three subcutaneous inoculations with irradiated MBP-reactive T cell clones resulted in depletion of circulating MBP-reactive T cells in patients with MS. Depletion of MBP-reactive T cells by T cell vaccination appeared to correlate with clinical improvement, as evidenced by a reduction in rate of relapse, expanded disability scale score (EDSS) and MRI lesion activities in relapsing-remitting patients (Medaer et al., 1995). Although no conclusion could be made from the pilot trial due to the limited number of MS patients studied, the excellent safety profile and the potential clinical benefit encouraged further clinical investigations. This preliminary clinical trial was undertaken to investigate whether depletion of circulating MBP-reactive T cells would be clinically beneficial to patients with MS.